Post-cardiac arrest care: An integrated approach to management after resuscitation

Table 1 Completed and ongoing major clinical trials on targeted temperature management

Trial	n	Rhythm	TTM strategy/goals	Primary endpoint	Primary endpoint event rates/effect sizes	Neurologic outcome(s)
HACA (2002)[28]	275	S	32-34 °C vs normothermia	Favorable neurologic outcome at 6 months	55% vs 39%; OR: 1.40 (95%CI: 1.08-1.81)a	Improved
Bernard et al[29], 2002	77	S	33 °C vs normothermia	Survival to discharge with good neurologic outcome	49% vs 26%b	Improved
TTM1 (2013)[30]	950	S/NS	33 °C vs 36 °C	All-cause mortality at end of trial	50% vs 48%; HR: 1.06 (95%CI: 0.89-1.28)	Similar
FROST-I (2018)[69]	291	S	32 °C vs 33 °C vs 34 °C	Favorable neurologic outcome at 6 months	46.4% vs 44.9% vs 42.3%c	Similar
HYPERION (2019)[33]	584	NS	33 °C vs normothermia	Favorable neurologic outcome at 90 days	10.2% vs 5.7%; absolute difference 4.5% (95%CI: 0.1-8.9)d	Improved
CAPITAL CHILL (2021)[32]	389	S	31 °C vs 34 °C	Survival with favorable neurologic outcome at 180 days	RR: 1.07; 95%CI: 0.86-1.33e	Similar
ISOCRATE (2021)[70]	120	S	Rewarming at 0.25 °C/hour vs 0.5 °C/hour	IL-6 levels at rewarming	No significant difference in IL-6 levels between groups	Similar
TTM2 (2021)[31]	1900	S/NS	33 °C vs normothermia (< 37.5 °C)	Death by 6 months	50% vs 48%; RR: 1.04 (95%CI: 0.94-1.14)f	No difference
ICE-CAP[71]	1800 (expected maximum)	S/NS	33 °C for 12 hours vs 24 hours vs 72 hours	Favorable neurologic outcome at 6 months	Pending	Ongoing
R-CAST OHCA[36]	380 (expected)	S/NS	34 °C vs normothermia (moderate-severe PCAS)	Favorable neurologic outcome at 30 days	Pending	Ongoing
STEPCARE (TEMPCARE part evaluates temperature)[68,72]	3500 (expected)	S/NS	Evaluating sedation, temperature, and hemodynamics	All-cause mortality at 6 months	Pending	Ongoing

^aP value < 0.01 vs normothermia.

^bP value < 0.05 vs normothermia.

^cP value = 0.83 for three-group comparison.

^dP value = 0.04 vs normothermia.

^eP value = 0.56 vs 34 °C.

^fP value = 0.37 vs normothermia.

Major completed and ongoing randomized clinical trials evaluating targeted temperature management (TTM) after cardiac arrest. Early landmark trials, including hypothermia after cardiac arrest and Bernard et al[29], demonstrated improved neurologic outcomes with hypothermia compared with normothermia in patients with shockable rhythms. Subsequent larger clinical trials, such as TTM1 and TTM2, reported no significant differences in mortality or neurologic outcomes between lower-temperature targets and active normothermia/fever-prevention strategies. More recent and ongoing studies are evaluating alternative temperature targets, duration of cooling, rewarming strategies, and multimodal post-cardiac arrest care approaches to refine patient selection and optimize neurologic recovery. n: Sample size during statistical analysis; Rhythm: Initial rhythm during cardiac arrest; TTM: Targeted temperature management; HACA: Hypothermia after cardiac arrest; S: Shockable; OR: Odds ratio; CI: Confidence interval; TTM1: Targeted temperature management-1 trial; NS: Non-shockable; HR: Hazard ratio; FROST-I: Finding the optimal cooling temperature after out-of-hospital cardiac arrest trial; HYPERION: Therapeutic hypothermia after cardiac arrest in nonshockable rhythm trial; CAPITAL CHILL: Moderate vs mild therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest trial; RR: Relative risk or risk ratio; ISOCRATE: Impact of speed of rewarming after cardiac arrest and therapeutic hypothermia; IL-6: Interleukin 6; TTM2: Targeted temperature management-2 trial; ICE-CAP: Influence of cooling duration on efficacy in cardiac arrest patients; R-CAST OHCA: Neurological outcomes with hypothermia vs normothermia in patients with moderate initial illness severity following resuscitation from out-of-hospital cardiac arrest trial; PCAS: Post-cardiac arrest syndrome; STEPCARE: Sedation, temperature and pressure after cardiac arrest and resuscitation trial.